This program project application represents a comprehensive collaborative effort by five senior investigators in two Departments of the University of Arizona to carry out a systematic investigation for the development of highly opioid receptor selective peptide ligands that will lead to nonaddictive opioid analgesics, and to new modalities for the treatment of pain, drug dependence and opioid withdrawal. We emphasize studies that will lead to new insights for the design of peptide and peptidomimetic structures that interact in a highly specific manner at CNS opioid receptors, and that will clarify the biochemical, pharmacological and physiological mechanisms related to specific opioid ligand-receptor interactions. A central hypothesis of this program is that highly potent, receptor selective and efficacious delta (and perhaps dynorphin/kappa) opioid peptides with high selectivity for delta receptor subtypes can either alone or in combination provide these new modalities. Given the complexities of opioid peptide-receptor interactions and their primary sites of action in the CNS, multiple chemical, biochemical, pharmacological and physiological experimental approaches will be used simultaneously. Strong collaborative interactions will be emphasized with the following major specific aims: (1) use of computer aided drug design of highly receptor selective and efficacious agonist peptide ligands for the delta and kappa (dynorphin) opioid receptors and receptor subtypes including the putative mu-deltacomplex, and application of these and various biophysical methods to design peptide analogues that can cross the blood brain barrier; 2) in vitro and in vivo pharmacology of opioid receptor specific ligands to determine their antinociceptive actions in several assays; 3) examine the ability of highly selective ligands for delta opioid receptor types and subtypes to modulate pain, dependency and withdrawal; 4) examine the biochemical similarities and difference between central and peripheral mu, delta, and kappa opioid receptors and their localization using highly specific ligands; 5) examine the metabolism, stability, distribution, bioconversion, and pharmacokinetics of highly delta, and perhaps kappa opioid peptide ligands and prodrugs for insight into design of suitable properties; 6) examine properties of highly selective opioid peptide ligands which will more effectively diffuse through membranes; 7) continue to develop and use core facilities to synthesize the large quantities of the highly receptor selective ligands, and to examine in detail the receptor selectivity, potency, biochemical mechanisms, and receptor localization of newly designed peptide ligands.